The asthma-anxiety connection

Respiratory Medicine 120 (2016) 44e53

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The asthma-anxiety connection Stefano R. Del Giacco a, *, Alessandra Cappai b, Luisanna Gambula a, Stefano Cabras c, d, Silvia Perra c, Paolo Emilio Manconi a, Bernardo Carpiniello e, Federica Pinna e a

Department of Medical Sciences “M. Aresu”, Allergy and Clinical Immunology Unit, University of Cagliari, Cagliari, Italy South London and Maudsley NHS Foundation Trust, London, United Kingdom c Department of Mathematics and Informatics, University of Cagliari, Cagliari, Italy d Department of Statistics, Carlos III University of Madrid, Madrid, Spain e Department of Public Health, Psychiatry Unit, University of Cagliari, Cagliari, Italy b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 28 March 2016 Received in revised form 16 September 2016 Accepted 20 September 2016 Available online 21 September 2016

Background: The literature reports a significant association between various mental disorders and asthma, in particular depression and/or anxiety, with some more robust data regarding anxiety disorders. However, the nature of this association remains largely unclear. Objectives: (1) To test the hypothesis of a specific association of anxiety and depressive disorder (according to the DSM-IV) with asthma and (2) to test the bidirectional hypothesis of causality between asthma and psychiatric disorders. Methods: One hundred ninety-two adults were compared with 192 control subjects matched according to main socio-demographic variables (i.e., gender, age, marital status, cohabiting/non-cohabiting, and BMI). Subjects with asthma were divided according to GINA and ACT classifications. All subjects underwent Structured Clinical Interviews for DSM-IV Axis I (SCID-I) diagnosis. Results: Significant association between asthma and lifetime anxiety disorders emerged (OR 3.03; p ¼ 0.003); no significant association with other psychiatric diagnosis emerged. Moreover, lifetime and current anxiety were associated with asthma severity levels (p < 0.01 and p ¼ 0.001 based on age). Asthma preceded anxiety in 48% of cases; in 52% of cases, anxiety preceded asthma, without significant group differences. The risk of asthma, particularly of severe, uncontrolled forms (p < 0.01), resulted higher in lifetime anxiety disorder patients (p ¼ 0.003 and p ¼ 0.001 based on age at onset). Current anxiety increased the risk of asthma, and that of an uncontrolled form (p < 0.05). Asthma increased the risk of lifetime anxiety disorders (p ¼ 0.002 and p ¼ 0.018 using ages). Intermittent asthma increased the risk of lifetime and current anxiety disorders (p < 0.01). Conclusions: Anxiety disorders, in particular Lifetime Anxiety Disorders, represent the only psychiatric disorder significantly associated with asthma, with a possible bidirectional, anxiety-asthma relationship, each of which can be caused or result from the other. © 2016 Elsevier Ltd. All rights reserved.

Keywords: Asthma Anxiety Depression Psychiatric disorders DSM-IV SCID

1. Introduction Asthma is a major global health problem affecting over 300 million people of all ages worldwide and represents a significant socio-economic burden [1e3]. Its prevalence continues to increase in many areas of the world. Asthma and psychological factors have been associated for centuries: Moses Maimonides, in his “Treatise

* Corresponding author. Department of Medical Sciences “M. Aresu”, Asse Didattico “E1” Medicina, Cittadella Universitaria, 09042, Monserrato, Cagliari, Italy. E-mail address: [email protected] (S.R. Del Giacco). http://dx.doi.org/10.1016/j.rmed.2016.09.014 0954-6111/© 2016 Elsevier Ltd. All rights reserved.

on Asthma,” defined asthma as “difficulty of breathing or a pain in the chest,” suggesting behavioural changes as one of the measures to cure it [4]. The literature reports a significantly greater prevalence of mental disorders in people with asthma, with a particular emphasis on those with depression and/or anxiety [5e7]. This association has important implications for these patients deriving from the presence of psychiatric comorbidity including symptom severity [8,9] and reduced asthma control [10,11]; lower quality of life [12]; low therapy adherence [6]; higher incidence of smoking, inactivity, and obesity [13]; and increased use of healthcare services and, therefore, an increase in financial burden [10,14]. However, the evidence about the association between asthma and mental

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disorders is not unequivocal, largely due to significant methodologic differences between studies (e.g., differences in study design, sampling, methods of psychiatric evaluation), only appearing sound where the asthma-anxiety association is concerned [15]. Thus, whether a specific association does exist between anxiety disorders and/or depression and asthma remains a question to be answered. Moreover, the evidence for an association between asthma and affective disorders raises an ongoing debate on the true nature of this relationship: whether asthma is associated with a higher risk of affective disorders, and/or whether affective disorders increase the risk of developing asthma [16]. Our study was performed based on a reliable methodology for the evaluation of psychiatric diagnosis to test the hypotheses that: (a) anxiety and/or depressive disorders are the psychiatric conditions specifically associated with asthma and (b) a bidirectional link exists between these disorders and asthma.

which better reflects the real clinical status of the patient in clinical practice. AC is multidimensional in nature, being characterized by symptoms, changes in pulmonary function, and effects on quality of life and functional ability [18]. The ACT (Asthma Control Test) [19,20], the well-known five-item survey to assess asthma control, was employed. The parameters considered in the questionnaire are daytime and nocturnal asthma symptoms, the use of rescue medications, and the effect of asthma on daily functioning. Each item includes five response options corresponding to a 5-point Likert-type rating scale, and the sum of the responses to the five items provides a score ranging from 5 (poor control of asthma) to 25 (complete control of asthma) [20]. The questionnaire was completed by patients under the supervision of the interviewer.

2. Methods

Following specific informed consent, all patients and controls underwent global psychiatric evaluation regarding the presence or absence of Axis I and II disorders according to the DSM-IV criteria using the Structured Clinical Interview for DSM-IV diagnosis of Axis I (SCID-I, Research version) [21] and the Structured Clinical Interview for DSM-IV diagnosis of Axis II disorders (SCID-II) [22]. Interviews were conducted by resident psychiatrists who were trained in the use of the instruments by a senior specialist (FP, BC); inter-rater reliability evaluated using Cohen's kappa [23] before the start of the study was no lower than 0.80 [5]. For the purpose of this study, we will discuss only results obtained through the SCID-I.

To test the abovementioned hypotheses, a case-control study was conducted on a clinical sample of asthma patients referred to a public health centre, who were compared to a group of individuals without asthma and matched according to the main social and demographic variables and body mass index (BMI). 2.1. Study subjects All consecutive adult asthma patients referred to the outpatient unit of the Allergy Centre of the University Hospital in Cagliari, Italy, in a 24-month period, were invited to participate in the study. Subjects affected by asthma who met the following criteria were enrolled: age 18e65 years and diagnosis of asthma. Patients affected by other severe somatic comorbidities (e.g., cardiac diseases, pulmonary diseases other than asthma, autoimmune diseases, past and current malignancies, neuromuscular disorders, and any other condition potentially influencing the respiratory function) and pregnant patients were excluded. Of the 134 patients that consented to participate, 96 were eligible (24 men, 72 women). Non-eligibility reasons after signing the informed consent form were mainly: (i) decided to not undergo the psychiatric interview; (ii) discovered further documentation of another disease or condition listed in the exclusion criteria; and (iii) pregnancy (1 case). Demographic, social, and clinical data were collected. Concurrently, during a 24-month period, an equal convenience sample comprising caretakers or relatives of patients or by members of the university hospital administrative staff was selected and used as a control group. All subjects were paired with the asthma patients according to sex, age (±4 years), marital status, cohabit status (cohabiting/non-cohabiting), education, and BMI (normal weight; overweight; and mild, moderate, or severe obesity). Control subjects affected by the same exclusion criteria were excluded. The Ethics Committee of the University of Cagliari approved the study. 2.2. Diagnosis of asthma Diagnosis of asthma was based on previous positivity to broncho-provocation tests (methacholine, mannitol) or on broncho-reversibility test. Diagnosis was made by a physician from our outpatient clinic or by an external Allergy or Respiratory Medicine Specialist. Severity of asthma at the time of diagnosis, according to previous GINA guidelines [17], was used to stratify patients. However, since GINA classification by severity levels applies to untreated patients, we also adopted the parameter of “asthma control” (AC),

2.3. Psychiatric assessment

2.4. Confounding factors The two groups were paired not only for gender and age, but also for other well-known potential confounding variables relevant for psychiatric disorders, such as marital status [24], cohabitation [25], education [26e28], and weight status, given that obesity and weight excess are associated with psychiatric disorders [29e46], such as eating disorders [35e37], depression [38,45], belowthreshold depressive and anxiety syndromes [39,40], anxiety [41,46], and personality traits and disorders [42e44]. 3. Statistical analysis Non-parametric analysis was first used to examine the association between asthma variables and psychiatric variables (current and lifetime diagnosis). For the purpose of our research, no specific direction in the relationship between asthma and psychiatric disorders is assumed. Statistical analysis included the calculation of the significance of the association between the asthma of a patient and his/her psychiatric status in a regression analysis setting in which there is a response variable and a set of explanatory factors. Some classic non-parametric tests such as Fisher's exact test for count data (in its generalized version: generalized Fisher's test) [47,48] and the permutation test [49] were employed when one variable was continuous and the other was categorical. Moreover, given that the main response variable, that is the condition of asthma, is a polytomous order variable, polytomous logistic regression [50] of the asthma variable over other variables representing the psychiatric status was employed. The odds ratios between cases and controls were also evaluated along with the goodness of fit of the model. Specifically, three different variables that describe the condition of asthma were considered: asthma (dichotomous: yes/no); ACT (ordinal variable with three levels: controlled asthma, partially controlled asthma, uncontrolled asthma); GINA severity levels (ordinal variable with four levels:

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intermittent asthma, mild persistent asthma, moderate persistent asthma, severe persistent asthma). Psychiatric dichotomous variables (present/not present) were grouped into seven categories of disorders: lifetime anxiety, current anxiety, lifetime mood, current mood, lifetime personality; others lifetime; others current (where “others” stands for any mental disorder other than those cited among those considered by SCID). To further strengthen the evidence of any association between asthma and mental disorders, ages of onset of asthma and mental disorders were considered. A description of such onset ages is provided by usual Kaplan-Meier estimations of survival functions, where survival is intended with respect to the onset of asthma and/or mental disorder. Finally, the classical Cox proportional hazard regression (CPHR) model has been used to assess significance of the risk factors in the increment of the hazard rate (or decrement of survival) of asthma and mental disorder. As the CPHR model is semi-parametric, the results are free from any specific hazard rate assumption. In the CPHR model and in the logistic regression, response and explanatory variables have been given, but these methods do not allow assessment if asthma (mental disorder) is the natural response to mental disorder (asthma). All data were analysed using statistical R software (R Core Team, 2014) [51]. 4. Results 4.1. Sample characteristics The socio-demographic characteristics and the weight status of the samples are reported in Table 1. Subjects examined (both cases and controls) are prevalently women (75%), with a mean age between 40 and 41 years, mostly with a good level of education (>60% with a high school or university degree), married (approx. 60%) and employed (approx. 65%). Approximately one-third of the sample is comprised of overweight or obese subjects. No significant differences were observed between cases and controls with regard to distribution according to gender, age, marital status, education,

Table 1 Characteristics for cases and controls.

Age Median e yrs. Range e yrs. Gender e no. (%) Males Females Education e no. (%) Primary school Secondary school High school University not completed University degree General marital status e no. (%) Married/living with a cohabiting partner Not living with a cohabiting partner Professional status e no. (%) Employed Unemployed Student Pensioner Housewife Occasional jobs BMI category e no. (%) Normal weight Overweight Obesity type 1 Obesity type 2 Obesity type 3

Cases (N ¼ 96)

Controls (N ¼ 96)

40.50 (19.00e67.00)

41.00 (18.00e65.00)

24 (25) 72 (75)

24 (25) 72 (75)

8 (8) 24 (25) 35 (36) 3 (3) 26 (27)

8 (8) 24 (25) 35 (36) 3 (3) 26 (27)

56 (58) 40 (42)

56 (58) 40 (42)

60 (63) 9 (9) 7 (7) 6 (6) 12 (13) 2 (2)

66 (69) 3 (3) 6 (6) 3 (3) 16 (17) 2 (2)

62 (65) 18 (19) 13 (13) 1 (1) 2 (2)

62 (65) 18 (19) 13 (13) 1 (1) 2 (2)

work status, and BMI classes. 4.2. Association between mental disorders and asthma: non-parametric analysis Data on the association between asthma variables and psychiatric conditions (current and lifetime diagnosis) (Table 2) showed a significant association between asthma and lifetime anxiety disorders (OR, 3.03; p ¼ 0.003), but not between asthma and current anxiety disorders. Moreover, no other psychiatric diagnosis was found to be associated with asthma. With regard to ACT, the only significant association shown was between ACT and the presence of a lifetime anxiety disorder (Table 3) (p ¼ 0.007). However, the proportion of controlled and partially or totally uncontrolled asthma case subjects suffering from lifetime anxiety disorders is practically comparable, and the difference observed was substantial between cases (both controlled and partially controlled/uncontrolled) and controls. No other significant association with ACT emerged regarding current anxiety disorder or any other psychiatric diagnoses, whether lifetime or current. With regard to GINA, when the distribution of cases according to severity of asthma at the time of diagnosis was evaluated by the presence of a mental disorder, a close association between the presence of a lifetime anxiety disorder and asthma severity levels (p ¼ 0.0006) was found. This reflects the overall difference in distribution of anxiety between cases and controls, with an increased level of prevalence of lifetime anxiety disorders in patients with “intermittent” and “moderate and severe persistent” asthma (Table 4). A similar association was observed regarding current anxiety disorders (p ¼ 0.008), more represented among subjects with both intermittent and moderate/severe persistent asthma (Table 4). Even in this case, no other significant association emerged with regard other psychiatric diagnoses. 4.3. Association between asthma (response variable) and anxiety (explanatory variable) Logistic regression, in which asthmatic state was considered as the dependent variable and the diagnosis of current and lifetime anxiety as the explicative variables (Table 5), with socio-

Table 2 Prevalence rates of Psychiatric Disorders in Cases and Controls. [Fisher test's odds ratio and p-value.]. Cases (N ¼ 96)

Controls (N ¼ 96)

Lifetime anxiety e no. (%) Yes 31 (32) 13 (14) No 65 (68) 83 (86) Current anxiety e no. (%) Yes 20 (21) 11 (11) No 76 (79) 85 (89) Lifetime mood disorders e no. (%) Yes 17 (18) 12 (12) No 79 (82) 84 (88) Current mood disorders e no. (%) Yes 5 (5) 5 (5) No 91 (95) 91 (95) Personality disorders e no. (%) Yes 17 (18) 11 (11) No 79 (82) 85 (89) Other lifetime disorders e no. (%) Yes 10 (10) 4 (4) No 86 (90) 92 (96) Other current disorders e no. (%) Yes 9 (9) 2 (2) No 87 (91) 94 (98)

Odds ratio (95% CI)

P-Value

3.03 (1.41e6.84)

0.003

2.03 (0.86e5.01)

0.11

1.50 (0.63e3.69)

0.42

1 (0.22e4.50)

1

1.66 (0.68e4.18)

0.30

2.66 (0.73e12.07)

0.16

4.83 (0.96e47.13)

0.05

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Table 3 Prevalence rates of Psychiatric Disorders in Controls and in controlled and partially controlled/uncontrolled asthma according to ACT. [Fisher test's p-value.]. Controls (N ¼ 96) Lifetime anxiety e no. (%) Yes 13 (14) No 83 (86) Current anxiety e no. (%) Yes 11 (11) No 85 (89) Lifetime mood disorders e no. (%) Yes 12 (12) No 84 (88) Current mood disorders e no. (%) Yes 5 (5) No 91 (95) Personality disorders e no. (%) Yes 11 (11) No 85 (89) Other lifetime disorders e no. (%) Yes 4 (4) No 92 (96) Other current disorders e no. (%) Yes 2 (2) No 94 (98)

Controlled asthma (N ¼ 63)

Partially controlled and uncontrolled asthma (N ¼ 33)

P-Value

21 (33) 42 (67)

10 (30) 23 (70)

0.007

13 (21) 50 (79)

7 (21) 26 (79)

0.197

8 (13) 55 (87)

9 (27) 24 (73)

0.115

2 (3) 61 (97)

3 (9) 30 (91)

0.461

10 (16) 53 (84)

7 (21) 26 (79)

0.347

5 (8) 58 (92)

5 (15) 28 (85)

0.099

5 (8) 58 (92)

4 (12) 29 (88)

0.039

Table 4 Prevalence rates of psychiatric disorders in Controls and different GINA severity levels. [Fisher test's p-value.]. Controls (N ¼ 96) Lifetime anxiety e no. (%) Yes 13 (14) No 83 (86) Current anxiety e no. (%) Yes 11 (11) No 85 (89) Lifetime mood e no. (%) disorders Yes 12 (12) No 84 (88) Current mood e no. (%) disorders Yes 5 (5) No 91 (95) Personality disorders e no. (%) Yes 11 (11) No 85 (89) Other lifetime disorders e no. (%) Yes 4 (4) No 92 (96) Other current disorders e no. (%) Yes 2 (2) No 94 (98)

Intermittent (N ¼ 28)

Mild persistent (N ¼ 44)

Moderate and severe persistent (N ¼ 24)

P-Value

14 (50) 14 (50)

9 (20) 35 (80)

8 (33) 16 (67)

0.0006

10 (36) 18 (64)

4 (9) 40 (91)

6 (25) 18 (75)

0.008

3 (11) 25 (89)

8 (18) 36 (82)

6 (25) 18 (75)

0.377

0 (0) 28 (100)

3 (7) 41 (93)

2 (8) 22 (92)

0.501

5 (18) 23 (82)

8 (18) 36 (82)

4 (17) 20 (83)

0.593

3 (11) 25 (89)

4 (9) 40 (91)

3 (12) 21 (88)

0.251

3 (11) 25 (89)

4 (9) 40 (91)

2 (8) 22 (92)

0.083

Table 5 Association of Anxiety as independent variable and Asthma as dependent variable. Results of Regression Analysis. [Regression coefficients, standard errors and p-values for the logistic regressions.]. Dependent variable

Independent variable

Beta coefficient

Std. error

P-value

Asthma ACT GINA Asthma ACT GINA

Lifetime anxiety Lifetime anxiety Lifetime anxiety Current anxiety Current anxiety Current anxiety

1.114 0.870 1.112 0.077 1.279 0.999

0.370 0.317 0.317 0.796 0.565 0.526

0.003 0.006 <0.001 0.047 0.024 0.058

demographic and BMI variables considered as possible confounding factors, showed a significantly higher risk of suffering from asthma in patients with a lifetime anxiety disorder (p ¼ 0.003). Using the level of control of the asthma (ACT) as the dependent variable, the ordinal logistic regression results show that suffering from a lifetime anxiety disorder increases the risk of

being affected by uncontrolled asthma (p ¼ 0.006). Considering the “severity of asthma” (GINA) as the dependent variable, ordinal logistic regression demonstrates how a lifetime anxiety disorder tends to increase significantly the risk of suffering a more severe form of asthma (p < 0.001). Moreover, current anxiety increases the risk of asthma (p ¼ 0.047) and of being affected by an

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uncontrolled form of asthma (p ¼ 0.024). 4.4. Association between anxiety (response variable) and asthma (explanatory variable) Considering the psychiatric condition as the dependent variable and the asthma state as the explicative variable (Table 6), regression analysis showed in age-matched conditions, how the risk of having a lifetime anxiety disorder was increased by the presence of asthma (p ¼ 0.002). Furthermore, having controlled asthma increased the risk of developing a lifetime anxiety disorder, but only in female subjects (p ¼ 0.001). Considering the severity of asthma evaluated through GINA, data show that intermittent asthma increases significantly the risk of being affected by both a lifetime (p < 0.001) and current (p ¼ 0.004) anxiety disorder. 4.5. Bidirectional relationship between asthma and anxiety according to age at onset In the subgroup of subjects with asthma affected by lifetime anxiety disorders, the age at onset of the psychiatric disorder was compared with the age at onset of asthma. Age at onset of the anxiety disorder was obtained through the SCID-I structured clinical interview, whereas for asthma, it corresponded to the age at diagnosis. Of a total of 31 affected subjects, both with asthma and an anxiety disorder, onset of asthma preceded the anxiety disorder in 48% of cases; in the remaining 52%, anxiety preceded the onset of asthma, without any significant differences between the two groups. Using age at onset, anxiety was also found to be a risk factor for asthma, conditionally on all available information from the socio-demographic variables (see Table 7). In particular, lifetime anxiety is a risk factor (p ¼ 0.001) for asthma, increasing this risk 3.7 times (95% C.I.: 1.6e8.4). The Kaplan-Meier estimation of survival curve for asthma onset of these subjects is significantly higher than in those affected by lifetime anxiety (see Fig. 1-left). Similarly, considering age at onset, asthma was found to also be a risk factor for anxiety conditionally on all available information from the socio-demographic variables (see Table 8). In particular, asthma is a risk factor (p ¼ 0.018) for anxiety, with a 2.1 times increase of the risk of the disorder (95% C.I.: 1.1e3.9). The KaplanMeier estimation of survival curve of these subjects based on age

at onset of anxiety is significantly higher than in those affected by asthma (see Fig. 1-right). 5. Discussion A significant association between mental disorders and asthma, in particular depression and/or anxiety, is reported in the literature [5e7,52]. These data emerge from both population and clinical studies, although substantial methodological problems may limit the relevance of results. Indeed, population studies, whose strength is generally found in the large cohorts of individuals studied, suffer from relevant design limitations, such as the clinically uncontrolled, mainly self-reported, diagnosis of asthma [13,53e61]. Moreover, many of these studies based psychiatric diagnoses on self-evaluation questionnaires [13,54,57,62], clinical evaluation scales that do not allow a categorical psychiatric diagnosis [63], or structured clinical interviews administered by lay (i.e., nonclinical) interviewers [11,12,58,61]. Other population studies, irrespective of the psychiatric evaluation methods employed, concern only anxiety and/or depressive disorders [13,54,57,61,63,64]. In summary, in the literature, we found only a single population study using structured clinical interviews for psychiatric disorder and a medical diagnosis for asthma [65]. Alternatively, studies of clinical populations, which have the strength of a controlled diagnosis of asthma, are often burdened by some limitations such as the use of self-evaluation instruments for psychiatric diagnosis [66e68] or on clinical evaluation scales that do not allow a categorical psychiatric diagnosis [69,70]; other studies are focused on anxiety and/or depressive disorders only [69e75], and some have not used control groups [11,16,65,69,70,72,76e88]. Finally, some clinical studies involved only special populations such as paediatric [89] and/or adolescents patients [90]. To our knowledge, this is the first clinical study to present data on the association of current and lifetime Axis I mental disorders according to DSM-IV, evaluated through the use of a semistructured clinical interview conducted by clinicians, in a population of asthma patients with a clinically controlled diagnosis and compared to a healthy control group matched for sociodemographic variables and weight status (BMI) in order to avoid the possible confounding effect due to the co-presence of obesity [61]. In this regard, it should be underlined that several studies demonstrated the association between specific psychiatric syndromes or states such as eating disorders [35e37], depression [38], below-threshold depressive and anxiety syndromes [39,40],

Table 6 Association of Asthma as independent variable and Anxiety as dependent variable. Results of Regression Analysis. [Regression coefficients, standard errors and p-values for the logistic regressions.]. Dependent variable

Independent variable

Beta coefficient

Std. error

P-value

Lifetime anxiety

Age Asthma Age Asthma ACT controlled ACT partially controlled or uncontrolled Sex male Age Age GINA intermittent GINA mild persistent GINA moderate or severe Age GINA intermittent GINA mild persistent GINA moderate or severe Age

0.042 1.152 0.034 0.717 1.379 0.795 0.748 0.043 0.034 1.969 0.563 1.070 0.044 1.508 0.226 0.857 0.034

0.015 0.378 0.017 0.412 0.424 0.497 0.482 0.015 0.016 0.501 0.490 0.538 0.016 0.518 0.620 0.577 0.017

0.005 0.002 0.042 0.082 0.001 0.109 0.121 0.006 0.042 <0.001 0.250 0.047 0.005 0.004 0.715 0.138 0.049

Current anxiety Lifetime anxiety

Current anxiety Lifetime anxiety

Current anxiety

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Table 7 Explanatory variables of Asthma according to its age of onset: Regression Analysis. [Regression coefficients, standard errors and p-values for the Cox proportional hazard model. Also exponential of coefficients along with their 95% Confidence Intervals are shown. Effects must be interpreted with respect to their alias (the category not shown).]. Explanatory variable

Category

Response: Age at first asthma episode Gender Female Education Primary school Secondary school University not completed University degree General marital status Non-cohabiting Professional status Employed Unemployed Student Pensioner Occasional jobs BMI category Overweight Obesity type 1 Obesity type 2 Obesity type 3 Lifetime anxiety Yes Lifetime mood disorders Yes Personality disorders Yes Other lifetime disorders Yes Current anxiety Yes Current mood disorders Yes Other current disorders Yes

Coefficient

Std. error

P-value

Exp (coeff.)

95% conf. interval

0.247 0.533 0.131 0.155 0.494 0.084 0.280 0.811 1.558 0.147 0.124 0.308 0.355 0.396 0.504 1.319 0.008 0.146 1.939 0.957 0.164 2.204

0.270 0.471 0.292 0.659 0.293 0.268 0.383 0.510 0.608 0.580 0.848 0.316 0.341 1.085 0.811 0.413 0.360 0.376 1.168 0.459 0.581 1.201

0.360 0.258 0.654 0.815 0.092 0.754 0.464 0.112 0.010 0.800 0.884 0.331 0.297 0.715 0.534 0.001 0.981 0.698 0.097 0.037 0.777 0.067

1.281 0.587 1.140 0.857 1.638 1.087 1.324 2.249 4.749 1.159 0.883 0.735 0.701 1.486 0.604 3.741 0.992 1.157 0.144 0.384 0.848 9.057

0.754 0.233 0.643 0.236 0.923 0.643 0.625 0.828 1.442 0.371 0.167 0.395 0.359 0.177 0.123 1.665 0.490 0.553 0.015 0.156 0.272 0.861

2.176 1.477 2.020 3.117 2.909 1.838 2.804 6.112 15.643 3.615 4.659 1.367 1.368 12.466 2.958 8.405 2.007 2.420 1.419 0.945 2.651 95.293

Fig. 1. Conditional Kaplan-Meier estimations of survivals functions for asthma (left) and mental disorder (right) with respect to significant risk factors: lifetime anxiety for asthma and asthma for mental disorder.

symptoms of anxiety [41], personality traits and disorders [42e44], and obesity. In particular, consensus exists on the relationship between obesity and depression, with important implications in terms of prevention, early diagnosis, and treatment. A condition of obesity/overweight has been found to increase the risk of

depression, and depression has been found to be predictive of future development of obesity, with an increased risk of 58% [45]. Similarly, other studies have found a relationship between obesity and anxiety disorders [46]. Moreover, obesity has been associated with both respiratory difficulty and asthma in various ways

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Table 8 Explanatory variables of Anxiety according to its age of onset: Regression Analysis. [Regression coefficients, standard errors and p-values for the Cox proportional hazard model. Also exponential of coefficients along with their 95% Confidence Intervals are shown. Effects must be interpreted with respect to their alias (the category not shown).]. Explanatory variable

Category

Response: Age at first psychiatric episode Asthma Case Gender Female Education Primary school Secondary school University not completed University degree General marital status Non-cohabiting Professional status Employed Unemployed Student Pensioner Occasional jobs BMI category Overweight Obesity type 1 Obesity type 2 Obesity type 3

Coefficient

Std. error

p-value

Exp (coeff.)

95% conf. interval

0.751 0.548 0.643 0.366 1.157 0.227 0.055 0.100 0.498 17.897 0.297 1.121 0.354 0.284 0.661 0.527

0.319 0.438 0.634 0.377 1.075 0.441 0.345 0.448 0.594 4601.208 0.686 0.852 0.449 0.436 1.109 0.790

0.018 0.210 0.310 0.332 0.282 0.606 0.872 0.824 0.402 0.997 0.666 0.189 0.431 0.515 0.551 0.504

2.119 0.578 0.526 1.442 3.179 0.797 1.057 0.905 1.646 0.000 1.345 3.068 0.702 0.752 1.936 1.694

1.135 0.245 0.152 0.689 0.387 0.336 0.538 0.376 0.514 0.000 0.351 0.577 0.291 0.320 0.220 0.360

[91e93]. The common assumption is that weight increase occurs because asthma patients avoid physical exercise, as it could trigger their symptoms. Furthermore, obesity could increase the risk of gastro-oesophageal reflux, which in turn could trigger an asthma attack. Greater respiratory difficulty in asthma patients could be caused by “organic” rather than by functional damage, as obesity can reduce residual pulmonary function capacity by up to 500 mL. The association between airway hyper-responsiveness (AHR), pathognomonic to asthma, and changes in BMI, has been claimed as an explanation of the link between obesity and asthma, although this association remains controversial [94e99]. Finally, two metaanalyses [100,101] showed that being overweight or obese increases the odds of incident asthma in a dose-dependent manner; however, weight loss interventions show low-quality evidence of the beneficial effects of losing weight on asthma-related outcomes [101]. Our study demonstrates that the proportion of subjects diagnosed with a current or lifetime mental disorder was generally higher among those affected by asthma, compared to the healthy control subjects. However, the only common disorder for which a significantly higher prevalence among those with asthma was observed was lifetime anxiety disorder (32% vs. 14% of controls), with a three-fold greater risk. Moreover, non-parametric analysis showed how poor control of asthma is associated with a higher prevalence of lifetime anxiety disorders, whereas intermittent asthma, and, to a lesser degree, persistent and moderate/severe levels of asthma, are associated with a higher risk of lifetime anxiety disorders, and in a less evident manner, to current anxiety disorders. These results appear to confirm the particular association of asthma with anxiety disorders, but not depressive disorders, for which data in the literature are somewhat contradictory [15]. Our data are generally consistent with those of the only population study [102] that evaluated the association between mental disorders and asthma, using a structured clinical interview to assess psychiatric diagnosis and a clinical evaluation for the diagnosis of asthma. This study, involving a large sample of adult subjects, demonstrates how severe asthma is associated with a significantly higher risk of anxiety disorders, whereas current non-severe asthma is associated only to an increased risk of mood disorders, and non-severe lifetime asthma is associated to an increased risk of anxiety and somatoform disorders (22). Overall, our investigation substantially confirms the close relationship between asthma, particularly when uncontrolled or poorly controlled and of a moderate/severe degree, and anxiety disorders. Indeed, the

3.953 1.363 1.821 3.021 26.120 1.891 2.078 2.177 5.271 ∞ 5.162 16.308 1.694 1.770 17.033 7.963

association between anxiety (and/or various depressive disorders) and poorly controlled asthma has been repeatedly confirmed in several clinical studies, irrespective of methodologies employed [11,13,16,69,72,76,80,87]. Data on the association between higher levels of asthma severity (evaluated through GINA or other methods) and a more elevated probability of psychiatric disorders appear to be more heterogeneous, with positive results reported in some studies [61,72,77,79,84,86], negative results in others [16,75,78,81,85,87,88], whilst other studies show positive results, but only limited to subjective self-evaluation of anxiety and/or depression [83,84]. Confirmation of a significant association between asthmatic disorders and anxiety takes us back to the problem regarding the specificity of the link between asthma and anxiety disorders and of the nature of such an association [103]. In particular, it remains unclear whether the subsequent onset of anxiety manifestations is favoured by asthma or whether the latter favours the subsequent development of anxiety. In our study, data are in favour of a bidirectional hypothesis of causality, given that asthma precedes anxiety onset with almost the same frequency that the anxiety disorder precedes asthma onset; moreover, the latter is associated with an increased risk of lifetime anxiety disorders, but even being affected by an anxiety disorder, especially lifetime, is associated to an increased risk of suffering from asthma. Our data appear to substantially confirm what emerged from prospective longitudinal studies, namely that both clinically significant anxiety and/or depression constitute significant risk factors for developing asthma [104e107], and asthma may be the cause of subsequent affective disorders [108,109]. However, a recent study reports that a history of respiratory disease does not appear to confer an increased risk of depression or anxiety [110]. Above all, our study is in line with findings from longitudinal studies which are in favour of a bidirectional hypothesis: the large prospective population study including all people aged 15 years or above with a clinical diagnosis of asthma and of anxiety disorder according to ICD-9 codes by Lee et al. [64] and the longitudinal cohort study by Hasler et al. [111], both demonstrating the validity of the hypothesis of a bidirectional association between the two conditions. In addition, the large meta-analysis based on prospective studies investigating the relationship between psycho-social factors (stressful life events, anxiety and/or depression, scarce social support) and atopic disorders in children and adults [112] confirms the same findings. Hypothetical explanations for such a bidirectional relationship lead us to two substantial possibilities:

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both of the diseases can constitute a causative factor for the other through direct or indirect mechanisms, or both disorders can be explained based on mutual etiopathogenetic mechanisms. Asthma can lead to the development of anxiety disorders in relation to different putative mechanisms: the perception of threat due to a potentially lethal disease, the development of conditioning to anxiety induced by recurrent dyspnoea [113], and above all because of the unpredictability and occasionally uncontrollability of the respiratory manifestations, the progressive de-railing of respiratory receptors. The anxiogenic role of some anti-asthmatic drug types must also be considered, in particular of adrenergic agonists [111,114]. Anxiety disorders, in turn, especially in the event of early onset, could be causatively correlated to asthma through behavioural mechanisms (i.e., increased cigarette smoking [115]) or through biological mechanisms (i.e., hyperventilation, that can act as a “trigger” with respect to asthmatic attacks, determining bronchoconstriction) [106,111]. Furthermore, the mutual role of adverse childhood events as a risk factor not only for anxiety disorders, but also for the development of asthma [55,106], must be considered. Finally, the mechanisms of the effects of inflammation on the brain have become an area of intensive study, and evidence suggests that the high comorbidity between these disorders can be explained by the inflammation due to the mutual pathogenic mechanisms, linked to the complex psycho-neuro-immunological pathways involving mainly pro-inflammatory cytokines and imbalance towards the Th2 T-cell response [116e119]. 6. Conclusions The data obtained appear to be of a certain interest, considering several strong points of the study such as: clinical diagnosis of asthma; psychiatric diagnoses based on semi-structured interviews conducted by non-lay-interviewers (psychiatrists or residents in psychiatry) and the use of controls paired not only for the main socio-demographic variables confounding factors, but also for BMI. In this study, lifetime anxiety disorders represent the diagnosis most significantly and unequivocally associated with asthma, especially if inadequately controlled. Regression analysis showed that having a lifetime anxiety disorder bears an almost four-fold higher risk of having asthma, in particular uncontrolled and more severe asthma. Similarly, having asthma bears a more than twofold higher risk of having an anxiety disorder, confirming the possibility of a bidirectional relationship between anxiety and asthma, either of which can be the cause or consequence of the other, even though some underlying mutual etiopathogenetic mechanisms that explain the frequency of their association cannot be excluded. In either case, evidence of a close link between the two conditions confirms the need for a multi-disciplinary approach, not only with regard to research, but also in the daily clinical practice for the evaluation and treatment of the asthmatic patient, given the importance of anxiety as a comorbidity for the course of asthma, its prognosis, and response to therapy. Author contributions Study conception and design: SDG, AC, BC, FP. Statistical analysis of Data: SP, SC. Analysis and interpretation of data: all authors. Drafting the work: SDG, AC, BC, FP. Critical Revision for important intellectual content: all authors. Final approval of the version to be published: all authors. Agreement on accuracy and integrity of the work: all authors.

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Conflict of interest statement All the authors and collaborators declare no conflicts of interest involving the work under consideration for publication. Acknowledgements The authors acknowledge the following collaborators (in alphabetical order), who have made substantial contributions to the work reported in the manuscript: Data collection: Dr. Concetta Carruba-Toscano, Dr. Silvia Floris, MD, Dr. Anna Mancosu, Dr. Francesca Manunza, MD, Dr. Walter Orrù, MD, Dr. Stefania Palmieri, Dr. Enrico Zaccheddu, MD - Department of Public Health, Psychiatry Unit, University of Cagliari, Cagliari, Italy. Statistical analysis: Dr. Federico Argiolas, MD e ASL 4 Public Health Services, Cagliari, Italy. References [1] A. Custovic, S.L. Johnston, I. Pavord, M. Gaga, L. Fabbri, E.H. Bel, P. Le Souef, J. Lotvall, P. Demoly, C.A. Akdis, D. Ryan, M.J. Makela, F. Martinez, J.W. Holloway, S. Saglani, P. O'Byrne, A. Papi, S. Sergejeva, A. Magnan, S. Del Giacco, O. Kalayci, E. Hamelmann, N.G. Papadopoulos, EAACI position statement on asthma exacerbations and severe asthma, Allergy 68 (12) (2013) 1520e1531. [2] GINA, 2016-Pocket Guide for Asthma Management and Prevention, GINA Foundation, 2016. [3] C. Anandan, U. Nurmatov, O.C. van Schayck, A. Sheikh, Is the prevalence of asthma declining? Systematic review of epidemiological studies, Allergy 65 (2) (2010) 152e167. [4] F. Rosner, Moses Maimonides' treatise on asthma, Thorax 36 (4) (1981) 245e251. [5] W.J. Katon, L. Richardson, P. Lozano, E. McCauley, The relationship of asthma and anxiety disorders, Psychosom. Med. 66 (3) (2004) 349e355. [6] H. Baumeister, K. Balke, M. Harter, Psychiatric and somatic comorbidities are negatively associated with quality of life in physically ill patients, J. Clin. Epidemiol. 58 (11) (2005) 1090e1100. [7] R. Calam, L. Gregg, B. Simpson, J. Morris, A. Woodcock, A. Custovic, Childhood asthma, behavior problems, and family functioning, J. allergy Clin. Immunol. 112 (3) (2003) 499e504. [8] D.E. Shaw, A.R. Sousa, S.J. Fowler, L.J. Fleming, G. Roberts, J. Corfield, I. Pandis, A.T. Bansal, E.H. Bel, C. Auffray, C.H. Compton, H. Bisgaard, E. Bucchioni, M. Caruso, P. Chanez, B. Dahlen, S.E. Dahlen, K. Dyson, U. Frey, T. Geiser, M. Gerhardsson de Verdier, D. Gibeon, Y.K. Guo, S. Hashimoto, G. Hedlin, E. Jeyasingham, P.P. Hekking, T. Higenbottam, I. Horvath, A.J. Knox, N. Krug, V.J. Erpenbeck, L.X. Larsson, N. Lazarinis, J.G. Matthews, R. Middelveld, P. Montuschi, J. Musial, D. Myles, L. Pahus, T. Sandstrom, W. Seibold, F. Singer, K. Strandberg, J. Vestbo, N. Vissing, C. von Garnier, I.M. Adcock, S. Wagers, A. Rowe, P. Howarth, A.H. Wagener, R. Djukanovic, P.J. Sterk, K.F. Chung, U.B.S. Group, Clinical and inflammatory characteristics of the European UBIOPRED adult severe asthma cohort, Eur. Respir. J. off. J. Eur. Soc. Clin. Respir. Physiol. 46 (5) (2015) 1308e1321. [9] W. Katon, E.H. Lin, K. Kroenke, The association of depression and anxiety with medical symptom burden in patients with chronic medical illness, General Hosp. psychiatry 29 (2) (2007) 147e155. [10] L. Zhang, X. Zhang, J. Zheng, L. Wang, H.P. Zhang, L. Wang, G. Wang, Comorbid psychological dysfunction is associated with a higher risk of asthma exacerbations: a systematic review and meta-analysis, J. Thorac. Dis. 8 (6) (2016) 1257e1268. [11] F. Di Marco, P. Santus, S. Centanni, Anxiety and depression in asthma, Curr. Opin. Pulm. Med. 17 (1) (2011) 39e44. [12] H. Baumeister, N. Hutter, J. Bengel, M. Harter, Quality of life in medically ill persons with comorbid mental disorders: a systematic review and metaanalysis, Psychother. Psychosom. 80 (5) (2011) 275e286. [13] T.W. Strine, A.H. Mokdad, L.S. Balluz, J.T. Berry, O. Gonzalez, Impact of depression and anxiety on quality of life, health behaviors, and asthma control among adults in the United States with asthma, 2006, J. asthma off. J. Assoc. Care Asthma 45 (2) (2008) 123e133. [14] N. Hutter, A. Knecht, H. Baumeister, Health care costs in persons with asthma and comorbid mental disorders: a systematic review, General Hosp. psychiatry 33 (5) (2011) 443e453. [15] P.P. Roy-Byrne, K.W. Davidson, R.C. Kessler, G.J. Asmundson, R.D. Goodwin, L. Kubzansky, R.B. Lydiard, M.J. Massie, W. Katon, S.K. Laden, M.B. Stein, Anxiety disorders and comorbid medical illness, General Hosp. psychiatry 30 (3) (2008) 208e225. [16] K.L. Lavoie, A. Cartier, M. Labrecque, S.L. Bacon, C. Lemiere, J.L. Malo,

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